Structure of the New Spiroketal-Macrolide A82548A.

Kirst, Herbert A.; Larsen, Stephen H.; Paschal, Jonathan W.; Occolowitz, John L.; Creemer, Lawrence C.; Steiner, Jorge L. Rios; Lobkovsky, Emil; Clardy, Jon

doi:10.7164/antibiotics.48.990

Cited by 23 publications

(13 citation statements)

References 18 publications

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“…Previously, we isolated yokonolide A and a known related compound, A82548A (designated here as yokonolide B (YkB)) (Fig. 1A), from Streptomyces diastatochromogenes B59 as inhibitors of auxin-responsive gene expression using a GUS reporter line under the control of an auxin-inducible promoter (21,22). We report here the biological activities of YkB, demonstrate its specificity, and with it, connect the auxin signaling components to cell division and elongation.…”

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confidence: 99%

Yokonolide B, a Novel Inhibitor of Auxin Action, Blocks Degradation of AUX/IAA Factors

Hayashi

Jones

Ogino

et al. 2003

Journal of Biological Chemistry

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Yokonolide B (YkB; also known as A82548A), a spiroketal-macrolide, was isolated from Streptomyces diastatochromogenes B59 in a screen for inhibitors of ␤-glucoronidase expression under the control of an auxin-responsive promoter in Arabidopsis. YkB inhibits the expression of auxin-inducible genes as shown using native and synthetic auxin promoters as well as using expression profiling of 8,300 Arabidopsis gene probes but does not affect expression of an abscisic acid-and a gibberellin A 3 -inducible gene. The mechanism of action of YkB is to block AUX/IAA protein degradation; however, YkB is not a general proteasome inhibitor. YkB blocks auxin-dependent cell division and auxin-regulated epinastic growth mediated by auxin-binding protein 1. Gain of function mutants such as shy2-2, slr1, and axr2-1 encoding AUX/IAA transcriptional repressors and loss of function mutants encoding components of the ubiquitin-proteolytic pathway such as axr1-3 and tir1-1, which display increased AUX/IAAs protein stability, are less sensitive to YkB, although axr1 and tir1 mutants were sensitive to MG132, a general proteasome inhibitor, consistent with a site of action downstream of AXR1 and TIR. YkB-treated seedlings displayed similar phenotypes as dominant AUX/IAA mutants. Taken together, these results indicate that YkB acts to block AUX/IAA protein degradation upstream of AXR and TIR, links a shared element upstream of AUX/IAA protein stability to auxin-induced cell division/elongation and to auxin-binding protein 1, and provides a new tool to dissect auxin signal transduction.Auxin controls cell division, elongation, and differentiation and therefore, through its action at the level of the cell, exerts profound effects on growth and development throughout the life of the plant (1). Consistent with the diverse effects of auxin on growth and development is that the expression patterns of a number of genes are dramatically and rapidly altered by auxin application (2), suggesting that auxin ultimately regulates cell growth by controlling the profile of expressed genes. AUX/IAA genes comprise a 34-member gene family in Arabidopsis that is one of three known gene families that are regulated by auxin and implicated to play essential roles in auxin signaling (3, 4).The molecular and genetic studies on auxin signaling have revealed that auxin specifically enhances the transcription of many AUX/IAA genes within minutes without requiring de novo protein synthesis, suggesting that AUX/IAA genes are primary auxin-response genes (5, 6). AUX/IAA genes encode short lived nuclear proteins capable of heterodimerization with auxin-responsive factors (7) and are thought to act by negatively regulating the expression of early auxin-responsive genes including other members of the AUX/IAA family (3).Studies on Arabidopsis mutants with altered responses to auxin such as iaa3/shy2-2, iaa7/axr2-1, iaa17/axr3, iaa14/slr1, tir1, and axr1 revealed that the turnover rate of AUX/IAA proteins is in some way important in various developmental processes including ...

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confidence: 99%

Yokonolide B, a Novel Inhibitor of Auxin Action, Blocks Degradation of AUX/IAA Factors

Hayashi

Jones

Ogino

et al. 2003

Journal of Biological Chemistry

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“…Ossamycin differs from the other polyketide ATPase inhibitors in Fig 1 in that it bears the rare, highly reduced aminosugar l -ossamine attached to the ossamycin macrocycle at the C-8 position of the macrocycle. The ossamine moiety of ossamycin was originally reported to have the d - configuration [28] but X-ray crystallography of ossamycin later showed it to be in the l - configuration [6]. Subsequently, l -ossamine has been determined also to be a constituent of the aromatic polyketide frigocyclinone [29] and of spinosyn G, a minor component of the spinosyn complex from Saccharopolyspora spinosa [30,31].…”

Section: Resultsmentioning

confidence: 99%

“…The best-known and most widely-studied of these compounds are the 26-membered oligomycins/rutamycins [2], potent inhibitors of the mitochondrial F 1 F 0 -ATPase [3]. Various other macrocyclic polyketides related to the oligomycins/rutamycins have been isolated (Fig 1) by screening for antifungal, immunosuppressive or cytotoxic bioactivity, including for example the 24-membered dunaimycins [4], and the 22-membered cytovaricin [5], A82548A (also known as yokonolide B) [6], yokonolide A [7], phthoramycin [8], ushikulides A and B [9] and kaimonolide A [10], all produced by Streptomyces spp. and many of them by different strains of S .…”

Section: Introductionmentioning

confidence: 99%

“…The chemical structures of these compounds have been established by detailed NMR analysis. Also, assignment of relative and absolute stereochemistry at the multiple stereocentres has been achieved for representative compounds through single-crystal X-ray crystallography and elegant total synthesis [6, 11–14]. This has disclosed the striking structural consistency between the compounds of Fig 1.…”

Section: Introductionmentioning

confidence: 99%

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The biosynthetic pathway to ossamycin, a macrocyclic polyketide bearing a spiroacetal moiety

2019

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Ossamycin from Streptomyces hygroscopicus var. ossamyceticus is an antifungal and cytotoxic polyketide and a potent inhibitor of the mitochondrial ATPase. Analysis of a near-complete genome sequence of the ossamycin producer has allowed the identification of the 127-kbp ossamycin biosynthetic gene cluster. The presence in the cluster of a specific crotonyl-CoA carboxylase/reductase homologue suggests that the 5-methylhexanoate extension unit used in construction of the macrocyclic core is incorporated intact from the unusual precursor isobutyrylmalonyl-CoA. Surprisingly, the modular polyketide synthase uses only 14 extension modules to accomplish 15 cycles of polyketide chain extension, a rare example of programmed iteration on a modular polyketide synthase. Specific deletion of genes encoding cytochrome P450 enzymes has given insight into the late-stage tailoring of the ossamycin macrocycle required for the attachment of the unusual 2,3,4,6-deoxyaminohexose sugar l -ossamine to C-8 of the ossamycin macrocycle. The ossamycin cluster also encodes a putative spirocyclase enzyme, OssO, which may play a role in establishing the characteristic spiroketal moiety of the natural product.

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“…Auxin is probably the beststudied small molecule in plants, and its phenotypic and molecular effects have been examined for many decades. In an attempt to discover small molecule effectors of auxin responses in Arabidopsis, fermentation-derived natural products from the soil microorganism Streptomyces diastatochromogenes were screened for the ability to inhibit of auxin-responsive gene expression (Kirst et al, 1995;Hayashi et al, 2001). The researchers used transgenic Arabidopsis harboring the β-glucuronidase (GUS) reporter under the control of an auxin-inducible promoter to screened for compounds that inhibited reporter expression.…”

Section: Plant Growth Regulatorsmentioning

confidence: 99%

Powerful Partners: Arabidopsis and Chemical Genomics

Robert

Raikhel²,

Hicks³

2009

The Arabidopsis Book

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Chemical genomics (i.e. genomics scale chemical genetics) approaches capitalize on the ability of low molecular mass molecules to modify biological processes. Such molecules are used to modify the activity of a protein or a pathway in a manner that it is tunable and reversible. Bioactive chemicals resulting from forward or reverse chemical screens can be useful in understanding and dissecting complex biological processes due to the essentially limitless variation in structure and activities inherent in chemical space. A major advantage of this approach as a powerful addition to conventional plant genetics is the fact that chemical genomics can address loss-of-function lethality and redundancy. Furthermore, the ability of chemicals to be added at will and to act quickly can permit the study of processes that are highly dynamic such as endomembrane trafficking. An important aspect of utilizing small molecules effectively is to characterize bioactive chemicals in detail including an understanding of structure-activity relationships and the identification of active and inactive analogs. Bioactive chemicals can be useful as reagents to probe biological pathways directly. However, the identification of cognate targets and their pathways is also informative and can be achieved by screens for genetic resistance or hypersensitivity in Arabidopsis thaliana or other organisms from which the results can be translated to plants. In addition, there are approaches utilizing "tagged" chemical libraries that possess reactive moieties permitting the immobilization of active compounds. This opens the possibility for biochemical purification of putative cognate targets. We will review approaches to screen for bioactive chemicals that affect biological processes in Arabidopsis and provide several examples of the power and challenges inherent in this new approach in plant biology.

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Structure of the New Spiroketal-Macrolide A82548A.

Cited by 23 publications

References 18 publications

Yokonolide B, a Novel Inhibitor of Auxin Action, Blocks Degradation of AUX/IAA Factors

Yokonolide B, a Novel Inhibitor of Auxin Action, Blocks Degradation of AUX/IAA Factors

The biosynthetic pathway to ossamycin, a macrocyclic polyketide bearing a spiroacetal moiety

Powerful Partners: Arabidopsis and Chemical Genomics

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